Genetic and biochemical abnormalities of a-synuclein (a-Syn) are directly implicated in the pathogenesis of familial and sporadic forms of Parkinson's disease (PD). We have show that transgenic (Tg) mice expressing the A53T mutant oc-Syn, but not wild type (WT) or A30P, develop adult-onset disease with a progressive motor dysfunction, shortened life-span, and pathological features of human a-synucleinopathies. The studies of these mice and the cell lines expressing a-Syn have allowed us to identify potentially pathogenic biochemical alterations of a-Syn. Specifically, the disease in Tg mice is associated with the increase levels of detergent insoluble a-Syn aggregates and the accumulation of potentially pathogenic soluble oligomers. Our studies show that a-Syn is normally proteolytically truncated at the Carboxy-terminal region to generate a-Syn(AC)s. Correlative studies in human tissues, cell lines, and in vitro aggregation studies support the view that a-Syn(AC)s promotes the pathological aggregation of a-Syn. Our results also show that differential stabilization of a-Syn polypeptides may modulate vulnerability to a-synucleinopathies. Thus, factors that affect a-Syn metabolism modulate the vulnerability of selected neuronal populations to a-synucleinopathies in humans and in mice. In this proposal, we will explore the relationships between a-Syn metabolism/truncation and aggregation/oligomerization of a-Syn. To better define the relationships between of a-Syn metabolism, a-Syn aggregation and a-synucleinopathies, we propose following Aims. 1) Characterize proteolytic truncations of a-Syn and a-synucleinopathy-associated alterations of a-Syn in human and mouse. 2) Characterize the aggregation and oligomerization properties of truncated a-Syn variants using in vitro and in cell culture systems. 3) Characterize the primary sequence determinants and the cell biology of a-Syn metabolism/truncations. 4) Determine whether the known proteolytic systems are responsible for a-Syn metabolism/truncation in neuronal cells. [unreadable] [unreadable]